Today's abstractMar. 29, 2001, San Diego
9th International Symposium on Recent Advances in Hematopoietic Stem
Cell Transplantation
Results of Breast and Ovarian Cancer Patients Treated with High-Dose
Chemotherapy, Autologous Transplant and THERATOPE® Vaccine
Brenda M. Sandmaier, M.D.
Fred Hutchinson Cancer Research Center
and the University of Washington
Seattle, Washington
The success of high-dose chemotherapy followed by autologous stem cell
rescue for patients with solid tumors, such as breast and ovarian
cancer, is limited by high relapse rates. Dose intensification of
conditioning regimens has led to an increase in transplant-related
morbidity and mortality without a reduction of relapse rates. Relapses
may result from the incomplete eradication of endogenous malignant
cells by the treatment regimen or from the infusion of contaminating
tumor cells in the stem cell product. Current research in autologous
transplantation has focused on strategies to augment the immune system
after transplant to recognize tumor-specific antigens for the
prevention of relapse. One of the ways to deliver such active-specific
immunotherapy is through the administration of cancer-specific
vaccines. STn is a disaccharide antigen that is associated with the
MUC1 mucin core peptide that is present on a number of cancers. The
majority of ovarian and breast tumors are positive for STn, and
several studies of ovarian carcinoma have shown that serum STn level
is associated with outcome. Over 500 patients with metastatic
adenocarcinoma have been treated in Phase I/II clinical trials in a
nontransplant setting with THERATOPE® STn-KLH cancer vaccine. Patients
who produced the highest antibody titers against the mucin expressing
STn epitopes survived longer than patients who produced the lowest titers.
In general, immunotherapy may be most effective in controlling the
tumor when it is given to patients with a low tumor burden as
demonstrated in many animal studies. After high-dose chemotherapy
followed by autologous stem cell infusion, most patients will have a
low tumor burden. In our study, breast and ovarian cancer patients who
have undergone high-dose chemotherapy followed by autologous stem cell
rescue were treated with THERATOPE® STn cancer vaccine. Between
September 1995 and December 2000, 70 (17 high-risk stage II/III
breast, 37 stage IV breast, and 16 stage III/IV ovarian) cancer
patients were treated with high-dose chemotherapy followed by
autologous/syngeneic stem cell rescue and vaccination with THERATOPE®
STn-KLH with Detox-B. This was done in two sequential trials with the
first cohort of 40 patients receiving a total of five doses of the
vaccine and the second cohort of 30 patients receiving a total of six
vaccinations. The vaccine was very well tolerated with the most common
side effect of induration and erythema at the site of injection and
flu-like symptoms. The majority of patients treated developed an
increase in anti-STn titers with a sustained peak reached following
the fourth or fifth vaccination. In the first cohort, 63% of the
patients that received at least three immunizations demonstrated
specific T-cell proliferation to the STn antigen with 42% of the
patients able to mount a Th1 response. In addition, following
immunization, there was an increase in expression of lytic activity
against STn-bearing tumor targets. Using risk adjustment analysis to
compare the outcome of the first 40 breast and ovarian cancer patients
vaccinated with patients who were not, we found that vaccinated
patients appeared more likely to survive and less likely to relapse
(p=.07 and .10, respectively). The vaccinated patients with the
greatest specific lytic activity against an STn-positive tumor cell
line relative to nonspecific killing of another target cell line
tended to remain in remission longer than patients who displayed less
specific immune activity. With a median follow-up of more than 3
years, 21 of the 40 patients are alive, of whom 14 are in remission.
Overall, 45 of 70 patients treated are alive with 31 of 70 remaining
in remission. We concluded that the THERATOPE® vaccine was well
tolerated in breast and ovarian cancer patients after autologous
transplant. The clinical outcomes supported the conclusion that
THERATOPE® vaccination may further decrease the risk of relapse and
death, and thus further study is warranted. A randomized Phase III
multicenter study is currently underway and is approaching completion
of accrual of over 900 patients. In this study, stage IV breast cancer
patients are being treated with the vaccine after either conventional
chemotherapy or autologous transplant. The results of this Phase III
study will help to define the role of vaccines in patients with
malignancies.
Selected Bibliographic References
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Brenda M. Sandmaier, M.D.
https://www.biomira.com/sandmabs.html